Angiogenesis, the process of vascularization, has been implicated in a host of biological disorders including cancer, macular degeneration and arthritis. Spawned by the therapeutic potential associated with the inhibition of pathological angiogenesis, a flurry of activity has led to the discovery of a variety of antiangiogenic compounds which exhibit clinical utility. The discovery of 2-methoxyestradiol by Folkman et al has demonstrated evidence for potent antiangiogenic activity by the estrane steroid family and has provided the most potent endogenous mammalian inhibitor of tubulin polymerization yet discovered. (See U.S. Pat. No. 5,504,074.) Additionally, Fotsis et al have shown that of 2-methoxyestradiol exhibits in vitro anti-mitotic properties and reversible inhibition of cell proliferation while confluent cultures are unaffected. (See Fotsis, et. al. Nature 1994, 368, 237.) Preclinical and clinical trials have also shown 2-methoxyestradiol to be promising in the treatment of several angiogenic disorders.
2-Methoxyestradiol has been reported to exhibit antiangiogenic activity through the inhibition of tubulin polymerization by binding at the colchicine binding site. In contrast to 2-methoxyestradiol, colchicine exhibits minimal selectivity, is highly cytotoxic and as a result, its clinical use has been limited due to this low therapeutic index. Since the discovery of 2-methoxyestradiol, structure-activity relationship studies have yielded several 2-substituted estradiol derivatives that exhibit greater affinity for the colchicine binding site, as well as displaying greater cytotoxic responses in cancer cell lines. While the full clinical potential of 2-methoxyestradiol and these related compounds continues to be investigated, little remains known about the relationship between the observed antiangiogenic activity of 2-methoxyestradiol and its ability to bind to tubulin.